Disorders of Copper Metabolism in Children—A Problem too Rarely Recognized

**Background:** Copper is an essential trace element that serves as a cofactor for numerous enzymes, including cytochrome c oxidase, superoxide dismutase, dopamine β-hydroxylase, and lysyl oxidase. Both copper deficiency and excess lead to serious pathological conditions. Copper homeostasis depends on dietary intake, intestinal absorption, transport via ATP7A/ATP7B proteins, and proper excretion. Disorders of copper metabolism include Menkes disease (MD) and Wilson's disease (WD). Menkes disease, caused by mutations in the ATP7A gene on chromosome X, results in systemic copper deficiency due to impaired copper export from enterocytes into the bloodstream. This leads to deficient activity of copper-dependent enzymes, causing progressive neurodegeneration and connective tissue abnormalities. Wilson's disease, an autosomal recessive disorder caused by mutations in the ATP7B gene, impairs biliary copper excretion and incorporation of copper into ceruloplasmin, leading to toxic copper accumulation in the liver, brain, and other organs. The prevalence of WD is estimated at 1/30,000 births, while MD affects approximately 1/140,000 males. This review aims to analyze etiopathogenesis, clinical presentation, diagnostics, treatment, prognosis, and complications of these disorders based on recent literature.

**Methods:** This is a narrative review of the literature on copper metabolism disorders in children, focusing on Menkes disease and Wilson's disease. The authors synthesized information from published studies, case reports, and clinical guidelines to describe the pathophysiology, clinical features, diagnostic approaches, and therapeutic strategies for these conditions.

**Key Results:** Wilson's disease typically presents between 5 and 35 years of age with hepatic and/or neuropsychiatric manifestations. Hepatic symptoms range from asymptomatic laboratory abnormalities to acute liver failure, chronic hepatitis, and cirrhosis. Neurologic manifestations are predominantly extrapyramidal, with dysarthria being the most common first symptom. Kayser–Fleischer rings occur in approximately 40% of patients with hepatic manifestations and about 95% of those with neurologic manifestations. Diagnostic tests include reduced serum ceruloplasmin (in 80–95% of patients), increased 24-hour urinary copper excretion, hepatic copper concentration >250 µg/g dry weight, and molecular testing for ATP7B mutations. The Ferenci scoring system (minimum 4 points confirms diagnosis) aids in evaluation. Treatment involves chelating agents (penicillamine, trientine, tetrathiomolybdate) and zinc salts to inhibit intestinal copper absorption. Liver transplantation is indicated for acute liver failure with encephalopathy. Menkes disease manifests in infancy, typically diagnosed at 3–6 months of age, with characteristic sparse, lustreless, tangled hair (pili torti), cherubic facies, progressive psychomotor regression, seizures (focal clonic seizures progressing to infantile spasms and multifocal myoclonic seizures), hypotonia evolving to spasticity, and connective tissue abnormalities. Serum copper and ceruloplasmin levels are low. Neuroimaging shows cerebral and cerebellar atrophy, ventriculomegaly, tortuous intracranial vessels, and white matter changes. Treatment with copper-histidine supplementation is effective only when initiated soon after birth, before significant neurological damage occurs. Without treatment, death usually occurs before age 4 years. Occipital horn syndrome is a milder allelic variant with connective tissue abnormalities and occipital exostoses.

**Clinical Implications:** These copper metabolism disorders are underrecognized in pediatric populations, leading to delayed diagnosis and treatment. Early detection is critical: for Wilson's disease, prompt initiation of chelation therapy or zinc can prevent irreversible liver and neurological damage; for Menkes disease, neonatal copper-histidine therapy can improve neurological outcomes if started before symptom onset. The authors emphasize that general practitioners, neurologists, and gastroenterologists should maintain a high index of suspicion for these conditions. Specific recommendations include genetic testing for Wilson's disease in patients with serum ceruloplasmin below 120 mg/L and children with urinary copper excretion above 40 µg. The review highlights the need for awareness of atypical presentations and the importance of multidisciplinary management involving hepatology, neurology, and genetics.